The long term objectives of this grant are to understand the biological function of type VI collagen and to determine its role in disease processes. Type VI collagen, a heterotrimer of alpha1(VI), alpha2(VI) and alpha3(VI) chains, is the major component of beaded microfibrils found in almost all tissues. Changes in the expression or distribution of type VI collagen have been described in many pathological conditions, including fibrosis, diabetes, and osteoarthritis. Recently, mutations in type VI collagen genes have been found in a dominantly inherited, childhood onset genetic disorder, Bethlem myopathy. Under the auspices of this grant, we have defined the protein and gene structures for the three chains of human type VI collagen, delineated their binding interactions and expression patterns, and identified gene mutations in patients with Bethlelm myopathy. In this renewal application, the major focuses are to define the molecular and pathological mechanisms underlying type VI collagen gene mutations in Bethlem myopathy, and to examine in greater detail the role of type VI collagen in myogenesis. The specific aims are: (1) To define additional mutations in type VI collagen genes that cause Bethlem myopathy, and to examine how mutations in type VI collagen genes affect its biosynthesis, secretion, and microfibril assembly in dermal fibroblasts from affected individuals. (2) To study the role of type VI collagen in myogensis using in vitro differentiation models and to examine the interactions of type VI collagen with muscle proteins. (3) To generate transgenic mice with mutations in type VI collagen by gene targeting and to analyze the phenotypes of the mice with a focus on the development of skeletal muscle. These studies will lead to future development of diagnostic tests and therapeutic treatment for Bethlem myopathy.